Journal of the American Chemical Society
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(4) (a) Estes, D. P.; Grills, D. C.; Norton, J. R. J. Am. Chem. Soc. 2014,
cant primary kinetic isotope effect of 7±1 was observed by comꢀ
paring the rates of individual reactions run with NꢀH and NꢀD
isotopologs of 1. Taken altogether, these computational, spectroꢀ
scopic and kinetic data are consistent with a soft homolysis mechꢀ
anism of substrate activation involving rateꢀlimiting N–H abstracꢀ
tion from the Cp*2TiIIICl complex of 1 by TEMPO.
136, 17362. (b) Roth, J. P.; Mayer, J. M. Inorg. Chem. 1999, 38, 2760. (c)
Manner, V. W.; Mayer, J. M. J. Am. Chem. Soc. 2009, 131, 9874. (d)
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Semproni, S. P.; Milsmann, C.; Chirik, P. J.; J. Am. Chem. Soc. 2014, 136,
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Chem. Sci. 2014, 5, 916. (g) Miyazaki, S.; Kojima, T.; Mayer, J. M.; Fuꢀ
kuzumi, S. J. Am. Chem. Soc. 2009, 131, 11615. (h) Wu, A.; Mayer, J. M.
J. Am. Chem. Soc. 2008, 130, 14745. (i) Wu, A.; Masland, J.; Swartz, R.
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(5) Wood and Renaud reported pioneering synthetic examples of bond
weakening wherein stoichiometric borane complexes of water or aliphatic
alcohols serve as Hꢀatom donors to alkyl radicals: (a) Spiegel, D. A.;
Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am.
Chem. Soc. 2005, 127, 12513. (b) Pozzi, D.; Scanlan, E. M.; Renaud, P. J.
Am. Chem. Soc. 2005, 127, 14204.
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In conclusion, we have developed a conjugate amination proꢀ
tocol jointly catalyzed by Cp*2TiCl and TEMPO wherein a varieꢀ
ty of evidence suggests that substrate activation occurs through
complexationꢀinduced bond weakening. More generally, the comꢀ
patibility of the Cp*2TiCl/TEMPO system in this work suggest an
intriguing oneꢀelectron parallel to frustrated Lewis pair chemistry,
where sterically encumbered partners are not able to react with
one another, but still function cooperatively to effect substrate
bond activation. We anticipate that the elements of reaction deꢀ
sign presented herein are general and will provide a basis for the
development of other transformations that operate by a similar
principle.
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(6) (a) Warren, J. J.; Menzeleev, A. R.; Kretchmer, J. S.; Miller, T. F.,
III; Gray, H. B.; Mayer, J. M. J. Phys. Chem. Lett. 2013, 4, 519.
(b)Warren, J. J.; Mayer, J. M. J. Am. Chem. Soc. 2011, 133, 8544–8551.
(c) Manner, V. W.; DiPasquale, A. G.; Mayer, J. M. J. Am. Chem. Soc.
2008, 130, 7210. (d) reference 4b.
ASSOCIATED CONTENT
Supporting Information
(7) Warren, J. J.; Tronic, T. A.; Mayer, J. M. Chem. Rev. 2010, 110,
6961.
(8) (a) Campana, A. G.; Estevez, R. E.; Fuentes, N.; Robles, R.;
Cuerva, J. M.; Bunuel, E.; Cardenas, D.; Oltra, J. E. Org. Lett. 2007, 9,
2195. (b) Paradas, M.; Campaña, A. G.; Jiménez, T.; Robles, R.; Oltra, J.
E.; Buñuel, E.; Justicia, J.; Cárdenas, D. J.; Cuerva, J. M. J. Am. Chem.
Soc. 2010, 132, 12748. (c) Cuerva, J. M.; Campana, A. G.; Justicia, J.;
Rosales, A.; OllerꢀLopez, J. L.; Robles, R.; Cardenas, D. J.; Bunuel, E.;
Oltra, J. E. Angew. Chem. Int. Ed. 2006, 45, 5522.
(9) Huang, K.; Waymouth, R. M. J. Am. Chem. Soc. 2002, 124, 8200.
(10) (a) Huang, K.; Han, J. H.; Cole, A. P.; Musgrave, C. B.; Wayꢀ
mouth, R. M. J. Am. Chem. Soc. 2005, 127, 3807. (b) Huang, K.; Han, J.
H.; Musgrave, C. B.; Waymouth, R. M. Organometallics, 2006, 25, 3317.
(11) Bordwell, F. G.; Zhang, S.; Zhang, X.; Liu, W. J. Am. Chem. Soc.
1995, 117, 7092.
(12) The orbital origin of the transferring electron in these bond activaꢀ
tions (from titanium or localized in the NꢀH sigma bond) is not clear. We
favor concerted PCET as the mechanism based on prior work (including
references 6aꢀd) but acknowledge that HAT cannot be discounted.
(13) Alternatively, direct HAT from TEMPOꢀH to the Ti(IV) enolate
in Scheme 1 is calculated to be favorable by 14 kcal/mol and is a plausible
alternative mechanism for regeneration of the Ti(III) catalyst and TEMPO.
See supporting information for details.
(14) A reviewer suggested that thermal homolysis of the TiꢀO bond in
the titanium (IV) enolate followed by the HAT from TEMPOꢀH to the αꢀ
carbonyl free radical as a possible alternative mechanism.
(15) (a) Gansäuer, A.; Kube, C.; Daasbjerg, K.; Sure, R.; Grimme, S.;
Fianu, G. D.; Sadasivam, D. V.; Flowers, R. A., II. J. Am. Chem. Soc.
2014, 136, 1663. (b) Gansäuer, A.; von Laufenberg, D.; Kube, C.; Dahꢀ
men, T.; Michelmann, A.; Behlendorf, M.; Sure, R.; Seddiqzai, M.;
Grimme, S.; Sadasivam, D. V.; Fianu, G. D.; FlowersꢁII, R. A. Chem. Eur.
J., 2015 21, 280.
(16) For examples of titanocene–catalyzed reactions that tolerate ketone
functionality, see: (a) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2014, 136,
48. (b) Morcillo, S. P.; Miguel, D.; Campana, A. G.; Alvarez de Cienfueꢀ
gos, L.; Justicia, J.; Cuerva, J. M. Org. Chem. Front. 2014, 1, 15.
(17) Homolytic bond weakening is not a simple Lewis acid mediated
process. The NꢀH BDFE of Nꢀphenyl propionamide bound to BF3, a nonꢀ
redox active Lewis acid, is calculated to be 99 kcal/mol.
(18) All thermochemical parameters were also calculated using the
LANL2DZ functional, with very similar results See supporting inforꢀ
mation for details.
Experimental procedures, computational results, kinetic data and
characterization data. This material is available free of charge via
AUTHOR INFORMATION
Corresponding Author
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by Princeton University and the
NIH (R01 GM113105). We thank Iraklis Pappas, Brian Schaefer
and Paul Chirik for helpful discussions and a generous gift of
titanocene complexes. R.R.K is a fellow of the Sloan Foundation.
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(19) See supporting information for details.
(20) Calculations indicate that amide binding is endergonic by ~10
kcal/mol. See supporting information for details.
(21) A reviewer suggested that titanocenium cations may also be active
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